Stabilizing Dye-Sensitized Upconversion Hybrids by Cyclooctatetraene.

Lanthanide-doped upconversion nanoparticles (UCNPs) can convert low-energy near-infrared (NIR) light into high-energy visible light, making them valuable for broad applications. UCNPs often suffer from poor light-harvesting capabilities, which can be significantly improved by incorporating organic dye antennas. However, the dye-sensitized upconversion systems are prone to severe photobleaching in an ambient atmosphere. Here, we present a synergistic approach to mitigate photobleaching by introducing triplet state quencher cyclooctatetraene (COT). COT effectively suppresses the generation of singlet oxygen by quenching the triplet states of the dye and consumes the existing singlet oxygen through oxidant reactions. The inclusion of COT extends the half-life of IR806 by 4.7-times by preventing the oxidation of its poly(methylene) chains. Without significantly affecting emission intensity and dynamics, COT effectively stabilized dye-UCNPs, demonstrating a notable 3.9-fold increase in half-life under continuous laser irradiation. Our findings suggest a new strategy to enhance the photostability of near-infrared dyes and dye-sensitized upconversion nanohybrids.

Fluorogenic Chemical Probe Strategy for Precise Tracking of Mitochondrial Polarity.

Mitochondrial polarity is a critical indicator of numerous pathological and biological processes; thus, the development of fluorescent probes capable of targeting mitochondria and visually monitoring its polarity is of great significance. In this study, fluorescent probes were designed with a N, N-dialkylamino rhodol scaffold as the fluorophore sensitive to polarity environments, in which the alkyl chain length was adjusted rationally to obtain distinct polarity recognition modes. By integrating mitochondria targeting groups, three fluorogenic chemical probes ROML-1, ROML-2, and ROML-3 have been obtained, featuring the capability to target mitochondria and monitor its polarity precisely, dynamically and visually. The probes displayed a distinctive response to the alterations in polarity. ROML-1 and ROML-2 followed a turn-on pattern while ROML-3 was ratiometric. It has been demonstrated that the hypersensitivity to polarity and ratio fluorescence property of ROML-3 was attributed to methyl groups rather than ethyl or butyl groups. The introduction of short methyl chains made the dihedral angle between the dialkylamino substituent and fluorophore of ROML-3 (spirocyclic form) rotatable and enlarged the energy gap between the ground state and excited state, which has been validated by the results of density functional theory (DFT) calculations. Furthermore, ROML-3 was used to monitor mitochondrial polarity via confocal microscopy imaging, which revealed that compared to healthy cells the polarity of mitochondria in cancer cells was enhanced; meanwhile, the polarity of mitochondria in senescent cells was higher in contrast with young cells. The present probe ROML-3 has been proven to be an efficient tool to monitor mitochondrial polarity dynamics, which demonstrated potential significance in biomedical research and disease diagnosis.

Activatable Near-Infrared Fluorescence Probe for Hypochlorous Acid Detection in Early Diagnosis of Keloids.

Keloids represent pathologic conditions characterized by the presence of hyalinized collagen bundles and chronic inflammatory reactions. Recently, increased ROS production and disrupted apoptosis mechanisms in keloids have been reported, although the detailed mechanisms remain unclear. Herein, we developed a specific fluorescence probe, Pro-NBS, to investigate ClO- levels in keloids. The probe demonstrated high specificity for ClO- over other ROS and exhibited a strong linear detection relationship. Based on its performance, we focused on the TGF-ß pathway in the development of keloids. ROS upregulation was observed in keloid-derived fibroblasts. Using ClO- as an intrinsic overexpression marker, our probe effectively distinguished between normal fibroblasts and keloid-derived fibroblasts both in vitro and in vivo. Furthermore, Pro-NBS showed potential for monitoring the progression and evaluating the systematic therapy of abnormal scarring or keloids.

NSD2 modulates Drp1-mediated mitochondrial fission in chronic renal allograft interstitial fibrosis by methylating STAT1.

Renal interstitial fibrosis/tubular atrophy (IF/TA) is a prominent pathological feature of chronic allograft dysfunction (CAD). Our previous study has demonstrated that epithelial-mesenchymal transition (EMT) plays a significant role in shaping the development of IF/TA. Nuclear SET domain (NSD2), a histone methyltransferase catalyzing methylation at lysine 36 of histone 3, is crucially involved in the development and progression of solid tumors. But its role in the development of renal allograft interstitial fibrosis has yet to be elucidated. Here, we characterize NSD2 as a crucial mediator in the mouse renal transplantation model in vivo and a model of tumor necrosis factor-α (TNF-α) stimulated-human renal tubular epithelial cells (HK-2) in vitro. Functionally, NSD2 knockdown inhibits EMT, dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in mice. Conversely, NSD2 overexpression exacerbates fibrosis-associated phenotypes and mitochondrial fission in tubular cells. Mechanistically, tubular NSD2 aggravated the Drp-1 mediated mitochondrial fission via STAT1/ERK/PI3K/Akt signaling pathway in TNF-α-induced epithelial cell models. Momentously, mass spectrometry (MS) Analysis and site-directed mutagenesis assays revealed that NSD2 interacted with and induced Mono-methylation of STAT1 on K173, leading to its phosphorylation, IMB1-dependent nuclear translocation and subsequent influence on TNF-α-induced EMT and mitochondrial fission in NSD2-dependent manner. Collectively, these findings shed light on the mechanisms and suggest that targeting NSD2 could be a promising therapeutic approach to enhance tubular cell survival and alleviate interstitial fibrosis in renal allografts during CAD.

Optimizing timing for quantification of intracranial aneurysm enhancement: a multi-phase contrast-enhanced vessel wall MRI study.

OBJECTIVES: Aneurysm wall enhancement (AWE) on high-resolution contrast-enhanced vessel wall MRI (VWMRI) is an emerging biomarker for intracranial aneurysms (IAs) stability. Quantification methods of AWE in the literature, however, are variable. We aimed to determine the optimal post-contrast timing to quantify AWE in both saccular and fusiform IAs. MATERIALS AND METHODS: Consecutive patients with unruptured IAs were prospectively recruited. VWMRI was acquired on 1 pre-contrast and 4 consecutive post-contrast phases (each phase was 9 min). Signal intensity values of cerebrospinal fluid (CSF) and aneurysm wall on pre- and 4 post-contrast phases were measured to determine the aneurysm wall enhancement index (WEI). AWE was also qualitatively analyzed on post-contrast images using previous grading criteria. The dynamic changes of AWE grade and WEI were analyzed for both saccular and fusiform IAs. RESULTS: Thirty-four patients with 42 IAs (27 saccular IAs and 15 fusiform IAs) were included. The changes in AWE grade occurred in 8 (30%) saccular IAs and 6 (40%) in fusiform IAs during the 4 post-contrast phases. The WEI of fusiform IAs decreased 22.0% over time after contrast enhancement (p = 0.009), while the WEI of saccular IAs kept constant during the 4 post-contrast phases (p > 0.05). CONCLUSIONS: When performing quantitative analysis of AWE, acquiring post-contrast VWMRI immediately after contrast injection achieves the strongest AWE for fusiform IAs. While the AWE degree is stable for 36 min after contrast injection for saccular IAs. CLINICAL RELEVANCE STATEMENT: The standardization of imaging protocols and analysis methods for AWE will be helpful for imaging surveillance and further treatment decisions of patients with unruptured IAs. KEY POINTS: Imaging protocols and measurements of intracranial aneurysm wall enhancement are reported heterogeneously. Aneurysm wall enhancement for fusiform intracranial aneurysms (IAs) is strongest immediately post-contrast, and stable for 36 min for saccular IAs. Future multi-center studies should investigate aneurysm wall enhancement as an emerging marker of aneurysm growth and rupture.

Associations between atherosclerotic luminal stenosis in the distal internal carotid artery and diffuse wall thickening in its upstream segment.

OBJECTIVES: Significant atherosclerotic stenosis or occlusion in the distal internal carotid artery (ICA) may induce diffuse wall thickening (DWT) in the upstream arterial wall. This study aimed to assess the association of atherosclerotic steno-occlusive diseases in the distal ICA with DWT in the upstream ipsilateral ICA. METHODS: Individuals with atherosclerotic stenosis in the distal ICA, detected by carotid MR vessel wall imaging using 3D pre- and post-contrast T1 volume isotropic turbo spin-echo acquisition (T1-VISTA) sequence, were enrolled. The associations of vessel wall thickening, the longitudinal extent of DWT, enhancement of the upstream ipsilateral ICA, and stenosis degree in the distal ICA were examined. RESULTS: Totally 64 arteries in 55 patients with atherosclerotic steno-occlusive distal ICAs were included. Significant correlations were found between distal ICA stenosis and DWT in the petrous ICA (r = 0.422, p = 0.001), DWT severity (r = 0.474, p < 0.001), the longitudinal extent of DWT in the ICA (r = 0.671, p < 0.001), enhancement in the petrous ICA (r = 0.409, p = 0.001), and enhancement degree (r = 0.651, p < 0.001). In addition, high degree of enhancement was correlated with both increased wall thickness and increased prevalence of DWT in the petrous ICA (both p < 0.001). CONCLUSIONS: DWT of the petrous ICA is commonly detected in patients with atherosclerotic steno-occlusive disease in the distal ICA. The degree of stenosis in the distal ICA is associated with wall thickening and its longitudinal extent in the upstream segments. CLINICAL RELEVANCE STATEMENT: Diffuse wall thickening is a common secondary change in atherosclerotic steno-occlusive disease in the intracranial carotid. This phenomenon constitutes a confounding factor in the distinction between atherosclerosis and inflammatory vasculopathies, and could be reversed after alleviated atherosclerotic stenosis. KEY POINTS: • Diffuse wall thickening of the petrous internal carotid artery is commonly detected in patients with atherosclerotic steno-occlusive disease in the distal internal carotid artery. • The phenomenon of diffuse wall thickening could be reversed after stenosis alleviation. • Carotid artery atherosclerosis with diffuse wall thickening should warrant a differential diagnosis from other steno-occlusive diseases, including moyamoya diseases and Takayasu aortitis.

Development and Validation of an ADA-Tolerant Assay for Quantification of an Exatecan-Based ADC in Monkey Plasma.

BACKGROUND: The development of an anti-drug antibody (ADA)-tolerant pharmacokinetic (PK) assay is important when the drug exposure is irrelevant to toxicity in the presence of ADA. We aimed to develop and validate an ADA-tolerant assay for an exatecan-based antibody-drug conjugate (ADC) in monkey plasma. RESULTS: The assay tolerated 5.00 µg/mL of ADA at 12 µg/mL of ADC. Its accuracy and precision results satisfied the acceptance criteria. Furthermore, the assay was free from hook and matrix effects and exhibited good dilutional linearity. Additionally, the ADC in plasma samples was stable under different storage conditions. METHOD: An ADA-tolerant ADC assay was configured with an anti-payload antibody for capture, and a drug-target protein combined with a horseradish peroxidase (HRP)-labeled antibody against a drug-target-protein tag for detection. Samples were firstly acidified to dissociate drug and ADA complexes, and to convert the carboxylate form to the lactone form of exatecan molecules; then, the ADAs in the samples were removed with a naked antibody-coated microplate. The treated samples were further incubated with coated anti-payload antibody and captured ADC molecules were quantified by the detection reagent. The developed assay was optimized and validated against regulatory guidelines. CONCLUSIONS: The assay met both methodological and sample-related ADA tolerance requirements, and was applicable to a nonclinical study in cynomolgus monkeys.

Mindfulness-Based Interventions on Psychological Comorbidities in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, lifelong disease, so IBD patients are highly susceptible to negative emotions, such as anxiety and depression, resulting in a reduced quality of life. Mindfulness-based intervention (MBI) is widely used to reduce stress, anxiety and depression in people. Therefore, this study conducted a systematic review of mindfulness-based intervention training on anxiety, depression, and quality of life in patients with IBD through meta-analysis. METHODS: Search papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, and Embase databases. The search time limit was from the establishment of the database to May 2023. Randomized controlled trial studies of the effect of mindfulness intervention training on patients with IBD were screened, the included results were integrated and analyzed, and ReviewManager 5.4 was used for meta-analysis. RESULTS: A total of 14 studies with a total of 1030 IBD patients were included. A total of 10 studies showed that the anxiety of patients in the mindfulness intervention group was significantly reduced by (standard mean difference (SMD) = -0.73, 95% confidence interval (CI): -1.01 to -0.45) compared to the control group. 8 studies showed that the intervention group significantly reduced patients' depression (SMD = -0.60, 95% CI: -0.78 to -0.42). 7 studies showed that the patient's quality of life improved after mindfulness intervention (SMD = 0.66, 95% CI: 0.45-0.87). CONCLUSION: Mindfulness-based intervention training can improve anxiety, depression, and quality of life in patients with inflammatory bowel disease in the short term, but the long-term effects need to be confirmed by more randomized controlled trials.

Photoactivated Hydrogen Sulfide Donor with a Near-Infrared Fluorescence Report System for Accelerated Chronic Wound Healing.

Delayed wound healing is one of the major diabetes complications that occur in 25% of diabetic patients. Specific wound management and combination treatment are required to repair the wound, which still remains a challenge with few effective therapies available currently. In this work, a new H2S donor PRO-F, which is characterized by the capability to promote wound healing in diabetes, was designed. PRO-F can be activated by light without consuming endogenous substances and the accompanying fluorescent signal makes the real-time tracking of released H2S possible. PRO-F is able to deliver H2S in an intracellular environment with moderate release efficiency (50%), which presents cytoprotective effects against excessive reactive oxygen species (ROS) induced damage. Furthermore, the potential of PRO-F to enhance chronic wound healing was validated by employing diabetic models. This work provides new insights into the therapeutic role of H2S donors in complex wound conditions, which should advance the pathophysiological research associated with H2S.

Elevated Hemoglobin A1c Is Associated With Leaky Plaque Neovasculature as Detected by Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

BACKGROUND: Patients with diabetes have accelerated atherosclerosis progression, but the underlying mechanisms are not fully understood. Dynamic contrast-enhanced magnetic resonance imaging has allowed in vivo characterization of plaque neovasculature, which plays a critical role in plaque progression. We aimed to evaluate the impact of diabetes on carotid plaque neovasculature as assessed by dynamic contrast-enhanced magnetic resonance imaging. METHODS: Patients with recent ischemic stroke and ipsilateral carotid plaque underwent multicontrast magnetic resonance imaging for characterizing plaque morphology and dynamic contrast-enhanced magnetic resonance imaging for pharmacokinetic parameters of plaque neovasculature, including transfer constant (Ktrans, reflecting flow, endothelial surface area, and permeability) and fractional plasma volume (νp). RESULTS: Sixty-five patients were enrolled, including 30 patients with diabetes (years since diagnosis: median 5.0 [interquartile range, [3.0-12.0]) and 35 patients without diabetes. Subjects with diabetes had a greater plaque burden and a higher prevalence of high-risk characteristics. Additionally, carotid plaques in the subjects with diabetes showed higher Ktrans than those in the subjects without diabetes (0.100±0.048 min-1 versus 0.067±0.042 min-1, P=0.005) but νp was numerically lower in the subjects with diabetes (5.2±3.7% versus 6.2±4.3%, P=0.31). The association of diabetes with high Ktrans (ß=0.033, P=0.005) was independent of patient and plaque characteristics and remained largely intact after adjusting for serum lipids, glucose, or hs-CRP (high-sensitivity C-reactive protein). However, it became nonexistent after adjusting for hemoglobin A1c (ß=-0.010, P=0.49). CONCLUSIONS: Dynamic contrast-enhanced magnetic resonance imaging of carotid plaques suggested that plaque neovasculature in patients with diabetes is leaky, indicating enhanced capability of bringing blood constituents and facilitating extravasation of inflammatory cells, erythrocytes, and plasma proteins. Leaky plaque neovasculature correlated with hemoglobin A1c and may play a role in accelerated atherosclerosis progression in diabetes.

The efficacy and safety of anti-EGFR target agents in patients with potentially resectable metastatic colorectal cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: Adding anti-epidermal growth factor receptor (anti-EGFR) target agents to conversion therapy may improve the resection rates and survival of patients with potentially resectable metastatic colorectal cancer (mCRC). This study aims to analyze the efficacy and safety of additional anti-EGFR target agents. METHODS: A systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library. And all relevant studies published in English before January 2023 were collected to explore the impact of additional anti-EGFR targeted agent on the efficacy and safety of patients with potentially resectable mCRC (PROSPERO: CRD42022340523, https://www.crd.york.ac.uk/PROSPERO/ ). RESULTS: This study included a total of 8 articles, including 2618 patients. The overall response rate (ORR) and R0 resection rates of the experimental group were higher than those of the control group, while there was no significant difference in progression-free survival (PFS) and overall survival (OS) between the two groups. In RAS/KRAS wild-type patients, the ORR (RR: 1.20, 95% Cl: 1.02-1.41, p = 0.03), R0 resection rate (RR: 1.60, 95% Cl: 1.17-2.20, p = 0.003), PFS (HR: 0.80, 95% Cl: 0.68-0.93, p = 0.003), and OS (HR: 0.87, 95% Cl: 0.76-0.99, p = 0.031) of the experimental group were higher than those of the control group. While in KRAS mutant patients, there was no statistical difference between the two groups in ORR, R0 resection rate, PFS, and OS. CONCLUSION: The addition of anti-EGFR targeted agents can improve the prognosis of RAS/KRAS wild-type patients with potentially resectable mCRC, while KRAS mutant patients may not benefit. In addition, the overall safety factor was controllable.

Rational Design of a Dual-Channel Fluorescent Probe for the Simultaneous Imaging of Hypochlorous Acid and Peroxynitrite in Living Organisms.

Hypochlorous acid (HOCl) and peroxynitrite (ONOO-) are two important highly reactive oxygen/nitrogen species, which commonly coexist in biosystems and play pivotal roles in many physiological and pathological processes. To investigate their function and correlations, it is urgently needed to construct chemical tools that can track the production of HOCl and ONOO- in biological systems with distinct fluorescence signals. Here, we found that the coumarin fluorescence of coumarin-benzopyrylium (CB) hydrazides (spirocyclic form) is dim, and their fluorescence properties are controlled by their benzopyran moiety via an intramolecular photo-induced electron transfer (PET) process. Based on this mechanism, we report the development of a fluorescent probe CB2-H for the simultaneous detection of HOCl and ONOO-. ONOO- can selectively oxidize the hydrazide group of CB2-H to afford the parent dye CB2 (Absmax/Emmax = 631/669 nm). In the case of HOCl, it undergoes an electrophilic attack on the benzopyran moiety of CB2-H to give a chlorinated product CB2-H-Cl, which inhibits the PET process within the probe and thus affords a turn-on fluorescence response at the coumarin channel (Absmax/Emmax = 407/468 nm). Due to the marked differences in absorption/emission wavelengths between the HOCl and ONOO- products, CB2-H enables the concurrent detection of HOCl and ONOO- at two independent channels without spectral cross-interference. CB2-H has been applied for dual-channel fluorescence imaging of endogenously produced HOCl and ONOO- in living cells and zebrafish under different stimulants. The present probe provides a useful tool for further exploring the distribution and correlation of HOCl and ONOO- in more biosystems.

Activatable Near-Infrared Fluorescent Organic Nanoprobe for Hypochlorous Acid Detection in the Early Diagnosis of Rheumatoid Arthritis.

Early diagnosis of rheumatoid arthritis (RA) is crucial to prevent deterioration and improve the prognosis of disease outcome. However, current clinical diagnostic methods are unable to achieve accurate and early detection of RA. In this work, we designed an activatable organic nanoprobe (ONP-CySe) capable of specific and real-time imaging of ClO- in early RA. ONP-CySe comprises a near-infrared fluorescent selenomorpholine-caged cyanine dye as the sensing component and an amphiphilic triblock copolymer triphenyl phosphine derivative for mitochondria targeting. Our results showed that ONP-CySe successfully detected elevated levels of ClO- in the mitochondria of macrophages with high selectivity, low limit of detection (31.5 nM), excellent photostability, and good biocompatibility. Furthermore, ONP-CySe can also be used to monitor anti-inflammatory responses and efficacies of RA therapeutics, such as selenocysteine and methotrexate, in BALB/c mouse models. Therefore, our research proposes a universal molecular design strategy for the detection of ClO-, which holds potential for early diagnosis and drug screening for RA.

The contralateral progression in a cohort of Chinese adult patients with unilateral moyamoya disease after revascularization: a single-center long-term retrospective study.

BACKGROUND: Moyamoya disease (MMD) is a chronic progressive cerebrovascular disease mainly existing in the Asian population, which can be divided into unilateral and bilateral types. Contralateral progression has been reported in pediatric patients with unilateral MMD, while large series about contralateral progression in Chinese adult patients were rare. The goal of this study is to elucidate the clinical features and incidence of contralateral progression in Chinese MMD adult patients. METHODS: One hundred one Chinese adult patients with unilateral MMD who received surgery treatments between January 2015 and January 2017 in our hospital were enrolled in this study. This study contained 89 patients. Digital subtraction angiography was performed in all patients for initial diagnosis, and magnetic resonance angiography was repeated 6 months from the initial operation and then annually. Clinical characteristics, contralateral progression, and risk factors were studied. Previous related studies were also reviewed and meta-analyzed. RESULTS: Of these 89 patients, contralateral progression was identified in 8 patients (9.0%) within a median follow-up period of 63 months, which was lower than that in previous studies (25.9%). Single-factor analysis and multivariate analysis did not reveal significant risk factors related to the contralateral progression. CONCLUSION: The progress rate in this cohort of Chinese adult patients with unilateral MMD after revascularization was 9.0%, which indicates that some of the unilateral MMD were an early form of bilateral MMD rather than a separate condition. TRIAL REGISTRATION: This work was approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (approval number: Kelun-2017005).

An Activatable Near-Infrared Fluorescence Hydrogen Sulfide (H2S) Donor for Imaging H2S Release and Inhibiting Inflammation in Cells.

Hydrogen sulfide (H2S) is a vital endogenous signal molecule that exerts critical physiological functions such as biological regulation and cytoprotection. Despite significant progress in developing H2S donors, site-specific delivery and controllable release of H2S in biological systems remain a key challenge. Herein, we develop new Cys-triggered fluorescent H2S donor Pro-S that is composed of a dicyanoisophorone-based near-infrared (NIR) fluorescent dye and a thiocarbamate moiety. The H2S donor releases H2S under the attack of Cys, accompanied by the release of a fluorescent reporter, which enables the real-time capturing of H2S by fluorescence spectroscopy or microscopy. Pro-S exhibits strong NIR fluorescence enhancement (70-fold), excellent controllable H2S release (30 min), high H2S release efficiency (62%), and well live-cell compatibility, allowing for visualization of H2S release in cells and zebrafish. Moreover, Pro-S presents a good effect of anti-inflammation in RAW 264.7 cells. This work provides a new idea for the design of H2S donors, which may be beneficial to the comprehension of the potential mechanism of inflammation and optimization of treatment strategies.

An Edaravone-Guided Design of a Rhodamine-Based Turn-on Fluorescent Probe for Detecting Hydroxyl Radicals in Living Systems.

The hydroxyl radical (·OH), one of the reactive oxygen species (ROS) in biosystems, is found to be involved in many physiological and pathological processes. However, specifically detecting endogenous ·OH remains an outstanding challenge owing to the high reactivity and short lifetime of this radical. Herein, inspired by the scavenging mechanism of a neuroprotective drug edaravone toward ·OH, we developed a new ·OH-specific fluorescent probe RH-EDA. RH-EDA is a hybrid of rhodamine and edaravone and exploits a ·OH-specific 3-methyl-pyrazolone moiety to control its fluorescence behavior. RH-EDA itself is almost nonfluorescent in physiological conditions, which was attributed to the formation of a twisted intramolecular charge transfer (TICT) state upon photoexcitation and the acylation of its rhodamine nitrogen at the 3' position. However, upon a treatment with ·OH, its edaravone subunit was converted to the corresponding 2-oxo-3-(phenylhydrazono)-butanoic acid (OPB) derivative (to afford RH-OPB), thus leading to a significant fluorescence increase (ca. 195-fold). RH-EDA shows a high sensitivity and selectivity to ·OH without interference from other ROS. RH-EDA has been utilized for imaging endogenous ·OH production in living cells and zebrafishes under different stimuli. Moreover, RH-EDA allows a high-contrast discrimination of cancer cells from normal ones by monitoring their different ·OH levels upon stimulation with ß-Lapachone (ß-Lap), an effective ROS-generating anticancer therapeutic agent. The present study provides a promising methodology for the construction of probes through a drug-guided approach.

Association of Type 2 Diabetes Mellitus and Glycemic Control With Intracranial Plaque Characteristics in Patients With Acute Ischemic Stroke.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has shown to be associated with carotid plaque vulnerability. However, the impact of T2DM on intracranial artery atherosclerosis is not well-understood. PURPOSE: To evaluate the association of diabetes and glycemic control with intracranial atherosclerotic plaque characteristics identified by three-dimensional contrast enhanced MR vessel wall imaging in patients after acute ischemic stroke. STUDY TYPE: Prospective. POPULATION: Two hundred and eighty-eight symptomatic patients with acute ischemic stroke due to intracranial atherosclerotic plaque. FIELD STRENGTH/SEQUENCE: T1 WI volume isotropic turbo spin-echo acquisition sequence at 3.0 T. ASSESSMENT: Clinical profiles, blood biomarkers, the number of intracranial plaques, plaque enhanced score, and the features (location, luminal stenotic rate, intraplaque hemorrhage, length, burden, enhancement grade, and ratio) of culprit plaque (defined as the most stenotic lesion ipsilateral to the ischemic event) and nonculprit plaque were analyzed by three radiologists. STATISTICAL TESTS: Analysis of variance (ANOVA), Shapiro-Wilk normality test, Levene's test, ANOVA with Bonferroni post-hoc test, Kruskal Wallis H test with subsequent pairwise comparisons, chi-square with Bonferroni post-hoc test, generalized linear regression, Pearson correlation test, Kendall's W and intra-class correlation coefficient. RESULTS: Two hundred and twenty-five participants (age 60 ± 10 years, 58.7% male) with 958 intracranial plaques were included. More intracranial plaques were found in the T2DM group than the non-T2DM group (4.80 ± 2.22 vs. 3.60 ± 1.78, P < 0.05). Patients with poorly-controlled T2DM exhibited higher culprit plaque enhancement ratio than patients with well-controlled T2DM and non-T2DM (2.32 ± 0.61 vs. 1.60 ± 0.62 and 1.39 ± 0.39; respectively, P < 0.05). After adjusting for other clinical variables, T2DM was independently associated with increased intracranial plaque number (ß = 0.269, P < 0.05), and HbA1c level was independently associated with culprit plaque enhancement ratio (ß = 0.641, P < 0.05) in multivariate analysis. DATA CONCLUSION: T2DM is associated with an increased intracranial plaque number. Higher HbA1c is associated with stronger plaque enhancement. 3D contrast enhanced MR vessel wall imaging may help better understand the association of T2DM and glycemic control with intracranial plaque. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 3.

Endoscopic-assisted surgery versus microsurgery for pineal region tumors: a single-center retrospective study.

Pineal region tumors are extremely deep-seated and surgically challenging. The exposure and visualization obtained by microscopic surgery are relatively limiting. The application of high-definition endoscopes has recently provided neurosurgeons with a much more magnified and clearer view of the anatomy in the pineal region. The present study was performed to compare endoscopic-assisted surgery (ES) with microsurgery (MS) for pineal region tumors. We retrospectively analyzed patients admitted to our hospital for treatment of pineal region tumors from January 2016 to June 2019. All patients consented to undergo tumor resection with ES or MS. We compared the extent of resection, postoperative rate of hydrocephalus, complications, and outcomes between the two groups to estimate the safety and efficacy of ES. In total, 41 patients with pineal region tumors were divided into 2 groups: the ES group (n = 20) and MS group (n = 21). The rate of gross total resection was significantly higher in the ES than MS group (90.0% vs. 57.1%, p = 0.04). The rate of postoperative hydrocephalus was significantly lower in the ES than MS group (11.8% vs. 52.9%, p = 0.03). No significant differences were found in complications or the Karnofsky Performance Score between the two groups. ES can be used to safely and effectively achieve complete resection of pineal region tumors. In patients with obstructive hydrocephalus, ES provides a new way to directly open the aqueduct for cerebrospinal fluid recovery following tumor resection.

MKK4/MKK5-MPK1/MPK2 cascade mediates SA-activated leaf senescence via phosphorylation of NPR1 in Arabidopsis.

The mechanism by which endogenous salicylic acid (SA) regulates leaf senescence remains elusive. Here we provide direct evidence that an enhancement of endogenous SA level, via chemical-induced upregulation of ISOCHORISMATE SYNTHASE 1 (ICS1), could significantly accelerate the senescence process of old leaves through mediation of the key SA signaling component NON EXPRESSOR OF PATHOGENESIS RELATED GENES 1 (NPR1) in Arabidopsis. Importantly, by taking advantage of this chemically induced leaf senescence system, we identified a mitogen-activated protein kinase (MAPK) cascade MKK4/5-MPK1/2 that is required for the SA/NPR1-mediated leaf senescence. Both MKK4/5 and MPK1/2 exhibited SA-induced kinase activities, with MPK1/2 being the immediate targets of MKK4/5. Double mutants of mkk4 mkk5 and mpk1 mpk2 displayed delayed leaf senescence, while constitutive overexpression of the kinase genes led to premature leaf senescence. Such premature leaf senescence was suppressed when they were overexpressed in an SA synthesis defective mutant (sid2) or signaling detective mutant (npr1). We further showed that MPK1, but not MPK2, could directly phosphorylate NPR1. Meanwhile, MPK1 also mediated NPR1 monomerization. Notably, induction of disease resistance was significantly compromised in the single and double mutants of the kinase genes. Taken together, our data demonstrate that the MKK4/5-MPK1/2 cascade plays a critical role in modulating SA signaling through a complex regulatory network in Arabidopsis.

Correction to: MKK4/MKK5­MPK1/MPK2 cascade mediates SA­activated leaf senescence via phosphorylation of NPR1 in Arabidopsis.

Due to an unfortunate turn of events, the second co-corresponding author, Dr. Benke Kuai, was omitted from the original publication. The corrected authors' list and author contribution statement are published here and should be treated as definitive.